Note: Descriptions are shown in the official language in which they were submitted.
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A pharmaceutical formulation
This invention relates to a pharmaceutical formulation and in particular to a
stable
composition for a pharmaceutical dosage form containing olanzapine.
Olanzapine (2-methyl-4-(4-methyl-l-piperazinyl)-lOH-thieno[2,3-b] [1,5]
benzodiazepine)
is a psychotropic agent belonging to the class of drugs known as
thienobenzodiazepines.
Olanzapine is used for the treatment of schizophrenia and is indicated for the
prevention of
recurrence of manic episodes in patients with bipolar disorder whose manic
episode has
responded to olanzapine treatment.
US 4,115,568 discloses a general formula of thieno[1,5] benzodiazepines having
useful
CNS activity. US 5,229,382 discloses olanzapine per se as well its CNS
activity.
However, the current commercially available tablets are limited by a high rate
of
degradation of the drug. Olanzapine is known to suffer from problems
associated with the
intrinsic nature of olanzapine, e.g. moisture sensitivity, propensity for
discoloration,
metastability of various crystalline and amorphous forms and degradation after
compounding into tablets.
A number of attempts have been made to avoid the degradation of olanzapine.
For
example, WO 2005/009407 discloses a pharmaceutical composition containing
olanzapine
particles or powder in which the olanzapine particles or powder have a coating
comprising
lactose and/or mannitol. This document also discloses a pharmaceutical
composition
containing olanzapine and suitable excipients in which the olanzapine and
excipients have
a coating selected from carrageenan, sodium alginate, polyvinyl alcohol-
polyethylene
glycol graft copolymer, and a titanium dioxide-talc mixture.
There remains, however, a need to provide further and/or improved formulations
to avoid
degradation and discoloration of olanzapine formulations.
Accordingly, the present invention provides a pharmaceutical composition
comprising
olanzapine or a pharmaceutically acceptable salt thereof, and one or more
suitable
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pharmaceutical excipients, wherein the composition is coated with a coating
comprising
polyvinyl alcohol.
It has been found that surprisingly a coating containing polyvinyl alcohol
reduces the rate
of degradation of olanzapine when compounded into tablets.
The coating of the present invention contains polyvinyl alcohol which is
typically partially
hydrolysed (e.g. 85-89% hydrolysed). Polyvinyl alcohol is a known excipient,
see USP,
Ph.Eur. etc., and further explanation is considered unnecessary. Preferably
the polyvinyl
alcohol consists of vinyl alcohol/acetate monomers only and is not
copolymerised with any
other monomers. Preferably the polyvinyl alcohol is the sole polymer present
in the
coating. Preferably the coating further comprises titanium dioxide or talc and
particularly
preferably a combination of titanium dioxide and talc.
The coating preferably contains a minimum of 20 wt%, more preferably 30 wt%
and most
preferably 40 wt% of polyvinyl alcohol based on the total weight of the
coating. The
coating preferably contains a maximum of 80 wt%, more preferably 70 wt%, more
preferably 60 wt% and most preferably 50 wt% of polyvinyl alcohol based on the
total
weight of the coating.
When present, the coating preferably contains a minimum of 10 wt%, more
preferably 20
wt% and most preferably 30 wt% of titanium dioxide based on the total weight
of the
coating. The coating preferably contains a maximum of 60 wt%, more preferably
50 wt%,
and most preferably 40 wt% of titanium dioxide based on the total weight of
the coating.
When present, the coating preferably contain a minimum of 5 wt%, more
preferably 10
wt% and most preferably 20 wt% of talc based on the total weight of the
coating. The
coating preferably contains a maximum of 50 wt%, more preferably 40 wt%, and
most
preferably 30 wt% of talc based on the total weight of the coating.
Where the coating contains titanium dioxide and talc the combined total is
preferably a
minimum of 20 wt%, more preferably 30 wt% and most preferably 40 wt% based on
the
total weight of the coating. The coating preferably contains a maximum of 70
wt%, more
preferably 60 wt%, and most preferably 50 wt% of combined titanium dioxide and
talc
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based on the total weight of the coating. The ratio of titanium dioxide to
talc is preferably
90:10 to 10:90, more preferably 70:30 to 50:50 and most preferably about
60:40.
Olanzapine is a known compound and may be synthesised using the procedure
disclosed in
US 5,229,382.
The coating may be applied using known methods in the art. For example,
olanzapine or a
pharmaceutically acceptable salt thereof is combined with the appropriate
excipients and a
suspension, a dispersion or a solution of the coating composition is applied,
e.g. by
spraying, followed by drying the thus obtained coated composition. The
pharmaceutical
composition of the present invention is preferably a coated tablet. The
polyvinyl alcohol is
preferably contained in the coating only.
Olanzapine formulations may be formulated in various dosage forms containing 2
to 20 mg
of olanzapine and preferably 2.5, 5, 7.5, 10 or 15 mg of olanzapine.
The formulations contain pharmaceutically acceptable excipients which are well-
known in
the art. Suitable excipients include binders, disintegrants, fillers and
lubricants.
Examples
Preparation Example
A coating composition was prepared containing the following components:
Component % mass/g
Polyvinyl alcohol 45.52 455.20
Talc 20.00 200.00
Titanium dioxide 32.00 320.00
Xanthan gum 0.48 4.80
Soya lecithin 2.00 20.00
Total 100.00 1000.00
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Exam~le 1
Ingredient mg per tablet
Olanzapine 10
Lactose anhydrous 233.2
Microcrystalline Cellulose 64
Crospovidone 9.6
Magnesium stearate non bovine 3.2
After compounding, the tablets were coated with the coating composition
prepared in
Preparation Example at 3.2 mg/tablet.
Example 2
Tablets coated in accordance with Example 1 were tested for impurities at
different
temperatures and relative humidity.
% Total Impurities; 10 mg tablets
stored in alurninium/aluminium blisters
Tablets from Ex. 1 Zyprexa*
0-month LOQ** 0.14
3-month
25 C 60% RH LOQ 0.28
1-month
0.05 0.21
40 C 75% RH
*Commercially available tablet containing olanzapine
**Below limit of quantification
Example 3
20 mg tablets were compounded with the following composition.
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Ingredient mg per tablet
Olanzapine 20
Lactose anhydrous 304.3
Microcrystalline cellulose 85.3
Crospovidone 12.8
Magnesium stearate non bovine 4.3
426.7
The tablets were kept in an open Petri dish under visible light (VIS)
according to ICH
guidelines on photostability, over a period of one week. Olanzapine tablets
with coating
had been coated with coating formulation prepared in the Preparation Example.
% Total impurities in 20 mg tablets
Olanzapine Zyprexa
coated uncoated (coated)
0-month LOQ LOQ 0.07
1 week VIS LOQ 0.17 0.13
